NO173867B - ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE BENZAMIDES - Google Patents

ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE BENZAMIDES Download PDF

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NO173867B
NO173867B NO89892058A NO892058A NO173867B NO 173867 B NO173867 B NO 173867B NO 89892058 A NO89892058 A NO 89892058A NO 892058 A NO892058 A NO 892058A NO 173867 B NO173867 B NO 173867B
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formula
hydrogen
alkylcarbamylmethyl
reaction
acid
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NO89892058A
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NO173867C (en
NO892058D0 (en
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Anton Franz Josef Fliri
Rodney Caughren Schnur
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Pfizer
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Abstract

This application claims a series of compounds of the formula <CHEM> where HET is a heterocyclic group; n is an integer of 0 to 2 and R<1> is hydrogen or lower alkyl.

Description

Denne oppfinnelsen gjelder en analogifremgangsmåte for fremstilling av nye benzamidforbindelser og særlig, en serie N-heterocyklisk-4-guanylalkylbenzamider som er nyttige som proteaseinhibitorer. Disse forbindelsene har anvendelse som proteaseinhibitorer, særlig som antiplasminmidler. This invention relates to an analogous process for the preparation of new benzamide compounds and, in particular, to a series of N-heterocyclic-4-guanylalkylbenzamides useful as protease inhibitors. These compounds are used as protease inhibitors, in particular as antiplasmin agents.

US-patent 4.563.527 krever patentert en rekke amidinonaftylestere av furankarboksylsyre, benzofuran- og tiofenkarboksylsyrer som proteaseinhibitorer. US-patent 4.732.916 krever patentert en rekke 4-guanylmetylbenzamid-derivater som antiulcusmidler. US Patent 4,563,527 claims a series of amidinone naphthyl esters of furancarboxylic, benzofuran and thiophene carboxylic acids as protease inhibitors. US Patent 4,732,916 claims a number of 4-guanylmethylbenzamide derivatives as antiulcer agents.

Ifølge oppfinnelsen tilveiebringes en fremgangsmåte for fremstilling av terapeutisk aktive nye forbindelser med formel According to the invention, a method is provided for the production of therapeutically active new compounds of formula

eller et farmasøytisk godtagbart salt derav hvori HET er pyrimid-2-yl, dimetylpyrimid-4-yl, tiazol-2-yl, 4-fenyltiazol-2-yl, 4-fenyl-5-karbetoksytiazol-2-yl, 4-bifenylyltiazol-2-yl, pyrazin-2-yl, 6-klorpyrazin-2-yl, kinol-8-yl, 6-metoksykinol-8-yl, kinol-3-yl, 1,3,4-tiadiazol-2-yl, 3-fenyl-l,2,4-tiadiazol-5-yl, 5-trifluormetyl-1,3,4-tiadiazol-2-yl, 5-metylisoksazol-3-yl, 5-klorpyrid-2-yl, 4,5-dicyanoimidazol-2-yl, 5-klorbenzoksazol-2-yl, indazol-5-yl-2-karbetoksyindol-5-yl, 5-(p-nitrofenylsulfonyl)tiazol-2-yl eller et benzimidazol-2-yl med formel or a pharmaceutically acceptable salt thereof wherein HET is pyrimid-2-yl, dimethylpyrimid-4-yl, thiazol-2-yl, 4-phenylthiazol-2-yl, 4-phenyl-5-carbethoxythiazol-2-yl, 4-biphenylylthiazole -2-yl, pyrazin-2-yl, 6-chloropyrazin-2-yl, quinol-8-yl, 6-methoxyquinol-8-yl, quinol-3-yl, 1,3,4-thiadiazol-2-yl , 3-phenyl-1,2,4-thiadiazol-5-yl, 5-trifluoromethyl-1,3,4-thiadiazol-2-yl, 5-methylisoxazol-3-yl, 5-chloropyrid-2-yl, 4 ,5-dicyanoimidazol-2-yl, 5-chlorobenzoxazol-2-yl, indazol-5-yl-2-carbethoxyindol-5-yl, 5-(p-nitrophenylsulfonyl)thiazol-2-yl or a benzimidazol-2-yl with formula

der X er hydrogen eller metyl, Y er hydrogen, metyl, benzoyl, nitro, klor, fluor, brom eller metoksy og R<2> er hydrogen, where X is hydrogen or methyl, Y is hydrogen, methyl, benzoyl, nitro, chlorine, fluorine, bromine or methoxy and R<2> is hydrogen,

(Ci-Cgjalkyl, fenetyl, N- (C1-C3) alkylkarbamylmetyl, N,N-di (C^Cs) alkylkarbamylmetyl, N- ( C^ Cz) alkylkarbamyl, (C1-C3) alkoksykarbonylmetyl eller N-(p-klorbenzyl)-karbamylmetyl; n er et helt tall fra null til 2; og R<1> er hydrogen eller (C1-C3)alkyl. Disse forbindelser er proteaseinhibitorer som har særlig anvendelse som inhibitorer av serinprotease og er nyttige som antiplasmin- og antitrombinmidler. (Ci-Cgjalkyl, phenethyl, N-(C1-C3) alkylcarbamylmethyl, N,N-di (C^Cs) alkylcarbamylmethyl, N-( C^ Cz) alkylcarbamyl, (C1-C3) alkoxycarbonylmethyl or N-(p-chlorobenzyl )-carbamylmethyl; n is an integer from zero to 2; and R<1> is hydrogen or (C1-C3)alkyl. These compounds are protease inhibitors that have particular utility as inhibitors of serine protease and are useful as antiplasmin and antithrombin agents.

En foretrukket gruppe forbindelser er de hvori R<1> er hydrogen og n er null. Særlig foretrukket innen denne gruppe er forbindelsene der HET er pyrazin-2-yl, pyrimid-2-yl, 1,3,4-tiadiazol-2-yl, kinol-8-yl, tiazol-2-yl eller indazol-5-yl. A preferred group of compounds are those in which R<1> is hydrogen and n is zero. Particularly preferred within this group are the compounds where HET is pyrazin-2-yl, pyrimid-2-yl, 1,3,4-thiadiazol-2-yl, quinol-8-yl, thiazol-2-yl or indazol-5- yl.

En annen gruppe foretrukne forbindelser er de der HET er et benzimidazol-2-yl med formel Another group of preferred compounds are those in which HET is a benzimidazol-2-yl of formula

der X er hydrogen. Særlig foretrukket innen denne gruppe er forbindelsene der Y og R<2> begge er hydrogen, der Y er 5-nitro og R<2> er hydrogen, der Y er 5-klor og R<2> er hydrogen; eller der Y er hydrogen og R<2> er N,N-dietylkarbamylmetyl. where X is hydrogen. Particularly preferred within this group are the compounds where Y and R<2> are both hydrogen, where Y is 5-nitro and R<2> is hydrogen, where Y is 5-chloro and R<2> is hydrogen; or where Y is hydrogen and R<2> is N,N-diethylcarbamylmethyl.

Brukt som her, defineres uttrykket (C^-Cs)alkyl som alkyl som har ett til tre karbonatomer; tilsvarende uttrykk kan benyttes for å definere alkoksy, osv. As used herein, the term (C 1 -C 8 )alkyl is defined as alkyl having one to three carbon atoms; corresponding expressions can be used to define alkoxy, etc.

Forbindelsene med formel I fremstilles ifølge oppfinnelsen som angitt i kravets karakteristikk. The compounds of formula I are produced according to the invention as stated in the characteristic of the claim.

Det foretas således en acylering av den passende aminoheterocykliske forbindelse med et karboksyaktivert benzosyrederivat. An acylation of the appropriate aminoheterocyclic compound is thus carried out with a carboxy-activated benzoic acid derivative.

Den aktiverte syre kan bestå av et syrehalogenid eller en aktivert ester eller blandet anhydrid. De foretrukne acyleringsmidler er enten N-hydroksysuccinimidester eller syrekloridet. The activated acid may consist of an acid halide or an activated ester or mixed anhydride. The preferred acylating agents are either N-hydroxysuccinimide esters or the acid chloride.

Koblingsreaksjonen kan gjennomføres ved å bringe i kontakt ett mol av den passende benzokarboksylsyre N-hydroksysuccinimidester med fra 1 til 2 mol av den nødvendige aminoheterocykliske forbindelse og rundt 0,01 mol hydrokinon i et reaksjons-inert oppløsningsmiddel så som dimetylformamid, dimetylsulfoksyd eller N-metyl-2-pyrrolidon. Reaksjonsblandingen varmes i mørke i rundt 1 til 3 6 timer ved en reaksjonstemperatur på 20-180°C. Ved reaksjonens fullførelse, fortynnes reaksjonsblandingen med metanol, filtreres om nødvendig og filtratet påføres den protonerte form av en ionebytter-resin (pH 5-6) så som GC50 (Aldrich Chemical Co., Inc.). Resinproduktkomplekset fylles deretter i en kolonne og vaskes tilstrekkelig med metanol, vann, dimetylsulfoksyd, dimetylformamid eller actonitril eller blandinger av disse for å fjerne all den gjenværende, ikke-omsatte aminoheterocykliske forbindelse. The coupling reaction can be carried out by contacting one mole of the appropriate benzocarboxylic acid N-hydroxysuccinimide ester with from 1 to 2 moles of the required aminoheterocyclic compound and about 0.01 mole of hydroquinone in a reaction-inert solvent such as dimethylformamide, dimethylsulfoxide or N-methyl -2-pyrrolidone. The reaction mixture is heated in the dark for about 1 to 36 hours at a reaction temperature of 20-180°C. At the completion of the reaction, the reaction mixture is diluted with methanol, filtered if necessary and the filtrate is applied to the protonated form of an ion exchange resin (pH 5-6) such as GC50 (Aldrich Chemical Co., Inc.). The resin product complex is then loaded into a column and washed sufficiently with methanol, water, dimethylsulfoxide, dimethylformamide or actonitrile or mixtures thereof to remove all remaining unreacted aminoheterocyclic compound.

Produktet frigjøres fra resinkomplekset ved å vaske ut kolonnen med en 0,1 til 0,01 molar oppløsning av en syre så som saltsyre, hydrogenbromsyre, metansulfonsyre, melkesyre eller eddiksyre i slike oppløsningsmidler som vann, metanol eller acetonitril. Vaskevæskene samles og konsentreres. Produktet, isolert som saltet av syren som er vaskevæske, felles ut mens oppløsningen konsentreres og samles ved filtrering. Videre rensing kan gjennomføres ved omkrystallisering fra slike oppløsningsmidler som dimetylformamid, tetrahydrofuran, etylacetat, kloroform, dimetylsulfoksyd, N-metyl-2-pyrrolidon, dietyleter eller metanol eller blandinger derav. The product is released from the resin complex by washing out the column with a 0.1 to 0.01 molar solution of an acid such as hydrochloric acid, hydrobromic acid, methanesulfonic acid, lactic acid or acetic acid in such solvents as water, methanol or acetonitrile. The washing liquids are collected and concentrated. The product, isolated as the salt of the acid which is washing liquid, precipitates while the solution is concentrated and collected by filtration. Further purification can be carried out by recrystallization from such solvents as dimethylformamide, tetrahydrofuran, ethyl acetate, chloroform, dimethylsulfoxide, N-methyl-2-pyrrolidone, diethyl ether or methanol or mixtures thereof.

En variant av denne fremgangsmåte omfatter å bringe i kontakt ett mol av 4-guanidinobenzosyrederivatet som et syre-addisjonssalt med sileringsmidlet bis-trimetylsilylacetamid, fulgt av dannelse av syrekloridet ved bruk av tionylklorid. Syrekloridet behandles deretter i tetrahydrofuran med så mye som et to gangers overskudd av den passende aminoheterocykliske forbindelse eller et engangs overskudd pluss et overskudd av en syrefjerner så som trietylamin. Etter en reaksjonstid på rundt 3 0 minutter ved omgivelsenes temperatur, fortynnes reaksjonsblandingen med tilstrekkelig vann til å felle ut produktet som omkrystalliseres som beskrevet tidligere. A variation of this method involves contacting one mole of the 4-guanidinobenzoic acid derivative as an acid addition salt with the silating agent bis-trimethylsilylacetamide, followed by formation of the acid chloride using thionyl chloride. The acid chloride is then treated in tetrahydrofuran with as much as a twofold excess of the appropriate aminoheterocyclic compound or a onefold excess plus an excess of an acid scavenger such as triethylamine. After a reaction time of about 30 minutes at ambient temperature, the reaction mixture is diluted with sufficient water to precipitate the product which is recrystallized as previously described.

Forbindelser fremstillet ifølge den foreliggende oppfinnelse, hvori HET er Compounds prepared according to the present invention, wherein HET is

overføres til forbindelser der HET er transferred to connections where HET is

hvori R<2> er som definert men forskjellig fra hydrogen. wherein R<2> is as defined but different from hydrogen.

Acylering av benzimidazol-nitrogenet med isocyanater gjennomføres i et reaksjons-inert oppløsningsmiddel så som dimetylformamid, dimetylsulfoksyd, N-metyl-2-pyrrolidon. Reaksjonen kan gjennomføres fra rundt romtemperatur til 100°C. Reaksjonstiden er rundt 24 timer ved omgivelsenes temperatur og 30 minutter til noen timer ved forhøyede temperaturer. Acylation of the benzimidazole nitrogen with isocyanates is carried out in a reaction-inert solvent such as dimethylformamide, dimethylsulfoxide, N-methyl-2-pyrrolidone. The reaction can be carried out from around room temperature to 100°C. The reaction time is around 24 hours at ambient temperature and 30 minutes to a few hours at elevated temperatures.

Når isocyanatet omsettes med forbindelsene som er angitt, er det nødvendig å bruke syreaddisjonssaltet av guanidobenzamidreaktanten for å forhindre interaksjon mellom guanyldelen med isocyanatet. Videre foretrekkes det å benytte et overskudd av isocyanat for å hjelpe til ved fullførelse av reaksjonen, et forhold på 1 mol benzimidazolderivat per 5 mol isocyanat gir det ønskede produkt. When the isocyanate is reacted with the compounds indicated, it is necessary to use the acid addition salt of the guanidobenzamide reactant to prevent interaction of the guanyl moiety with the isocyanate. Furthermore, it is preferred to use an excess of isocyanate to aid completion of the reaction, a ratio of 1 mol of benzimidazole derivative per 5 mol of isocyanate gives the desired product.

Reaksjonsblandingen, ved slutten av reaksjonstiden, fortynnes med dietyleter og det utfelte produkt filtreres fra og renses. The reaction mixture, at the end of the reaction time, is diluted with diethyl ether and the precipitated product is filtered off and purified.

Alkylering av benzimidazol-nitrogenet gjennomføres mellom 1 mol av forbindelsen som inneholder benzimidazol-enheten og rundt 5 til 6 mol alkyleringsmiddel. I tillegg, gjør alkyleringen bruk av fra 1 til 4 ekvivalenter base per mol utgangsreagens. Slike baser omfatter alkalimetallalkoksyder og karbonater. Oppløsningsmidlet, reaksjonstidene og temperaturen er omtrent de samme for alkyleringsreaksjonen som for den tilsvarende acyleringsreaksjon. Alkylation of the benzimidazole nitrogen is carried out between 1 mole of the compound containing the benzimidazole unit and about 5 to 6 moles of alkylating agent. In addition, the alkylation makes use of from 1 to 4 equivalents of base per mole of starting reagent. Such bases include alkali metal alkoxides and carbonates. The solvent, reaction times and temperature are approximately the same for the alkylation reaction as for the corresponding acylation reaction.

Som tidligere angitt, omfatter den foreliggende oppfinnelse farmasøytisk godtagbare salter av de biologisk virksomme forbindelser. Slike salter er de som er ikke-toksiske ved de doser som administreres. Farmasøytisk godtagbare syreaddisjonssalter omfatter for eksempel hydrokloridet, hydrobromidet, hydrojodidet, sulfatet, bisulfatet, fosfatet, syrefosfatet, acetatet, laktatet, maleatet, mesylatet, fumaratet, citratet, syrecitratet, tartratet, bitartratet, succinatet, glukonatet og sakkaratsaltene. Vanlige fremgangsmåter for tilberedning av syreaddisjonssalter kan anvendes. As previously indicated, the present invention comprises pharmaceutically acceptable salts of the biologically active compounds. Such salts are those which are non-toxic at the doses administered. Pharmaceutically acceptable acid addition salts include, for example, the hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, maleate, mesylate, fumarate, citrate, acid citrate, tartrate, bitartrate, succinate, gluconate, and saccharate salts. Usual methods for the preparation of acid addition salts can be used.

Plasmin, et serinprotease-enzym som eksisterer i blodet, er resultatet av innvirkningen av plasminogenaktivator på pro-enzymet plasminogen. Plasmin spiller en viktig rolle ved kapillærblodstrømmen og ved oppløsningen av fibrin. Imidlertid, når dette enzymet er tilstede i unormale mengder forårsaker det blødningssykdommer. I slike tilfeller er bruken av et antiplasminmiddel meget viktig. Forbindelsene fremstillet ifølge den foreliggende oppfinnelse har denne antiplasminvirkningen som lett kan demonstreres ved analysen til H. Zimmerman, et al., Proe. Nati. Acad. Sei., 7_5, 750 Plasmin, a serine protease enzyme that exists in the blood, results from the action of plasminogen activator on the pro-enzyme plasminogen. Plasmin plays an important role in capillary blood flow and in the dissolution of fibrin. However, when this enzyme is present in abnormal amounts it causes bleeding disorders. In such cases, the use of an antiplasmin agent is very important. The compounds prepared according to the present invention have this antiplasmin activity which can be easily demonstrated by the analysis of H. Zimmerman, et al., Proe. Nati. Acad. Sei., 7_5, 750

(1978) . (1978).

Forbindelsene fremstillet ifølge den foreliggende oppfinnelse, kan administreres som antiplasminmidler enten ad oral eller parenteral administreringsvei med den første som foretrukket med hensyn på pasientens bekvemmelighet og komfort. Generelt administreres disse antiplasminforbindelser vanligvis oralt i doser som varierer fra rundt 6 mg til rundt 400 mg per kg kroppsvekt per dag og 1 mg til rundt 200 mg per kg kroppsvekt per dag gitt parenteralt; variasjoner vil nødvendigvis forekomme avhengig av tilstanden til pasienten som behandles og den spesielle forbindelse som administreres. Det må bemerkes at disse forbindelser kan administreres sammen med farmasøytisk godtagbare bærestoffer ad begge de veier som tidligere er angitt og at slik administrering kan gjennomføres i både enkle og multiple doser. The compounds prepared according to the present invention can be administered as antiplasmin agents either ad oral or parenteral route of administration with the former being preferred in view of patient convenience and comfort. In general, these antiplasmin compounds are usually administered orally in doses ranging from about 6 mg to about 400 mg per kg of body weight per day and 1 mg to about 200 mg per kg of body weight per day given parenterally; variations will necessarily occur depending on the condition of the patient being treated and the particular compound being administered. It must be noted that these compounds can be administered together with pharmaceutically acceptable carriers by both of the routes previously indicated and that such administration can be carried out in both single and multiple doses.

De nye forbindelser fremstillet ifølge oppfinnelsen, kan administreres oralt i en lang rekke forskjellige doseringsformer, det vil si, de kan tilberedes med forskjellige farmasøytisk godtagbare inerte bærestoffer i form av tabletter, kapsler, sugetabletter, pastiller, harde drops, pulvere, sprayer, vandige suspensjoner, eliksirer, siruper og lignende. Slike bærestoffer omfatter faste fortynningsmidler eller fyllstoffer, sterile vandige medier og forskjellige ikke-toksiske organiske oppløsningsmidler, osv. Dessuten, kan slike orale farmasøytiske preparater søtes eller tilsettes smaksstoffer ved hjelp av forskjellige midler av typen som vanligvis benyttes til slike formål. Generelt, er forbindelser fremstillet ifølge denne oppfinnelsen, tilstede i slike orale doseringsformer i konsentrasjonsnivåer som varierer fra rundt 0,5% til rundt 90% av vekten av den totale blanding, i mengder som er tilstrekkelige til å gi de ønskede enhetsdoser. The new compounds produced according to the invention can be administered orally in a wide variety of different dosage forms, that is, they can be prepared with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, pastilles, hard drops, powders, sprays, aqueous suspensions , elixirs, syrups and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. In addition, such oral pharmaceutical preparations may be sweetened or flavored by various agents of the type commonly used for such purposes. Generally, compounds prepared according to this invention are present in such oral dosage forms at concentration levels ranging from about 0.5% to about 90% by weight of the total composition, in amounts sufficient to provide the desired unit doses.

Når det gjelder oral administrering, kan tabletter som inneholder forskjellige excipienser så som natriumcitrat, kalsiumkarbonat og kalsiumfosfat, benyttes sammen med forskjellige sprengmidler så som stivelse og fortrinnsvis potet- eller tapiokastivelse, alginsyre og visse komplekse silikater, sammen med bindemidler så som polyvinylpyrrolidon, sakkarose, gelatin og gummi arabicum. I tillegg, er smøremidler så som magnesiumstearat, natriumlaurylsulfat og talk ofte meget nyttige til tabletteringsformål. Faste blandinger av en tilsvarende type kan også benyttes som fyll i myke og harde fylte gelatinkapsler; foretrukne materialer i denne sammenheng vil også omfatte laktose eller melkesukker, samt polyetylenglykoler med høy molekylvekt. Når vandige suspensjoner og/eller eliksirer ønskes til oral administrering, kan den essensielle aktive ingrediens i denne forenes med forskjellige søtnings- eller smaksmidler, farvestoffer av forskjellige typer og om det er ønsket, også emulgerings- og/eller suspensjonshjelpestoffer sammen med slik med slike fortynningsmidler som vann, etanol, propylenglykol, glycerin og forskjellige lignende kombinasjoner av disse. De følgende eksempler illustrerer oppfinnelsen men må ikke tolkes som begrensning for denne. For oral administration, tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate can be used together with various disintegrants such as starch and preferably potato or tapioca starch, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic. Additionally, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc are often very useful for tableting purposes. Solid mixtures of a similar type can also be used as filling in soft and hard filled gelatin capsules; preferred materials in this context will also include lactose or milk sugar, as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the essential active ingredient therein may be combined with various sweetening or flavoring agents, coloring agents of various types and, if desired, also emulsifying and/or suspension auxiliaries together with such diluents such as water, ethanol, propylene glycol, glycerin and various similar combinations thereof. The following examples illustrate the invention but must not be interpreted as limiting it.

Eksempel 1 Example 1

4-guanidino-N-(pyrazin-2-yl)benzamid-hydroklorid n = 0; R<1> = H; og HET = 2- pyrazinyl) 4-guanidino-N-(pyrazin-2-yl)benzamide hydrochloride n = 0; R<1> = H; and HET = 2- pyrazinyl)

En oppløsning av 1,84 g (19,2 mmol) 2-aminopyrazin, 3,0 g (9,6 mmol) 4-guanidinobenzosyre N-hydroksysuccinimidester og 300 mg hydrokinon i 25 ml N-metyl-2-pyrrolidon ble varmet i mørke under en inert atmosfære ved 170°C i 7 timer. Den avkjølte reaksjonsblanding ble fortynnet med 3 00 ml metanol og 3 ml pyridin og behandlet med 50 g CG50 ionebytter-resin (HH— form). Oppløsningen ble dekantert og behandlet med ytterligere 25 g resin. Oppløsningen ble igjen dekantert og behandlet med 25 g resin. Resin-fraksjonene ble fylt på en kolonne slik at den siste resin-fraksjonen ble fylt på først, den første sist. Kolonnen ble vasket ut med 2 1 metanol og deretter med 0,02N saltsyre i metanol. Fraksjonene som inneholdt produktet ble samlet og konsentrert i vakuum til et fast stoff. Resten ble løst opp i metanol og felt ut med dietyleter. Produktet ble filtrert fra, vasket med i-propanol og tørret, 232 mg, smp. 278-280°C. A solution of 1.84 g (19.2 mmol) of 2-aminopyrazine, 3.0 g (9.6 mmol) of 4-guanidinobenzoic acid N-hydroxysuccinimide ester and 300 mg of hydroquinone in 25 ml of N-methyl-2-pyrrolidone was heated in dark under an inert atmosphere at 170°C for 7 hours. The cooled reaction mixture was diluted with 300 ml of methanol and 3 ml of pyridine and treated with 50 g of CG50 ion exchange resin (HH- form). The solution was decanted and treated with a further 25 g of resin. The solution was again decanted and treated with 25 g of resin. The resin fractions were loaded onto a column so that the last resin fraction was loaded first, the first last. The column was washed out with 2 l of methanol and then with 0.02 N hydrochloric acid in methanol. The fractions containing the product were collected and concentrated in vacuo to a solid. The residue was dissolved in methanol and precipitated with diethyl ether. The product was filtered off, washed with i-propanol and dried, 232 mg, m.p. 278-280°C.

Eksempel 2 Example 2

Ved å bruke fremgangsmåten fra Eksempel 1 bortsett fra der det er angitt, og starte med de passende reagenser, ble de følgende forbindelser fremstillet som hydrokloridsaltene: Using the procedure of Example 1 except where indicated, and starting with the appropriate reagents, the following compounds were prepared as the hydrochloride salts:

Eksempel 3 Example 3

4-guanidino-N-(kinol-8-yl)benzamid 4-guanidino-N-(quinol-8-yl)benzamide

( HET = 8- kinolvl; n = 0; og R^ H) ( HET = 8-quinolvl; n = 0; and R^ H)

En blanding av 2 00 mg (0,92 mmol) 4-guanidinobenzosyre hydroklorid og 190 mg (0,93 mmol) bis(trimetylsilylacetamid i 2 0 ml tørr tetrahydrofuran ble varmet med tilbakeløp inntil en oppløsning var oppnådd og deretter avkjølt til romtemperatur. Tionylklorid (380 mg, 1,86 mmol) ble tilsatt og reaksjonsblandingen ble rørt i 5 minutter. 8-aminokinolin (67 0 mg, 4,64 mmol) ble tilsatt i 5 ml tetrahydrofuran og blandingen fikk røres i 30 minutter. Vann (0,2 ml) ble tilsatt til reaksjonsblandingen og de faste stoffer filtrert fra og løst opp i 60 ml metanol og 120 ml kloroform. Tilsetning av dietyleter felte ut det ønskede produkt, 153 mg, smp. 271-273°C. A mixture of 200 mg (0.92 mmol) of 4-guanidinobenzoic acid hydrochloride and 190 mg (0.93 mmol) of bis(trimethylsilylacetamide) in 20 mL of dry tetrahydrofuran was heated at reflux until a solution was obtained and then cooled to room temperature. Thionyl chloride (380 mg, 1.86 mmol) was added and the reaction mixture was stirred for 5 min. 8-Aminoquinoline (670 mg, 4.64 mmol) was added in 5 mL of tetrahydrofuran and the mixture was allowed to stir for 30 min. Water (0, 2 mL) was added to the reaction mixture and the solids filtered off and dissolved in 60 mL methanol and 120 mL chloroform Addition of diethyl ether precipitated the desired product, 153 mg, mp 271-273°C.

Eksempel 4 Example 4

Ved å anvende fremgangsmåten fra Eksempel 3 bortsett fra der det er angitt, og starte med de nødvendige reagenser, ble de følgende produkter fremstillet: Using the procedure of Example 3 except where indicated, and starting with the required reagents, the following products were prepared:

Eksempel 5 Example 5

4-guanidino-N-(5-klorimidazol-2-yl)-benzamid 4-guanidino-N-(5-chloroimidazol-2-yl)-benzamide

( HET = 5- klorimidazol- 2- yl; n = 0; og R<1> = H) (HET = 5-chloroimidazol-2-yl; n = 0; and R<1> = H)

En blanding av 970 mg (4,48 mmol) 4-guanidinobenzosyre og 910 mg (4,48 mmol) bis-trimetylsilylacetamid i tørr tetrahydrofuran ble varmet til tilbakeløp i fem minutter. Etter avkjøling av den resulterende oppløsning, ble tionylklorid, 1,07 g (8,95 mmol) tilsatt fulgt etter 20 minutter av tilsetning av 1,5 g (8,95 mmol) 2-amino-5-klorimidazol og 1,81 g (17,9 mmol) trietylamin i 10 ml tetrahydrofuran. Etter 16 timer ved romtemperatur ble 0,4 0 ml vann tilsatt og de faste stoffer ble filtrert fra, vasket med kloroform og omkrystallisert fra metanol-kloroform-dietyleter, 435 mg, smp. 263-265°C. A mixture of 970 mg (4.48 mmol) of 4-guanidinobenzoic acid and 910 mg (4.48 mmol) of bis-trimethylsilylacetamide in dry tetrahydrofuran was heated to reflux for five minutes. After cooling the resulting solution, thionyl chloride, 1.07 g (8.95 mmol) was added followed after 20 minutes by the addition of 1.5 g (8.95 mmol) of 2-amino-5-chloroimidazole and 1.81 g (17.9 mmol) of triethylamine in 10 ml of tetrahydrofuran. After 16 hours at room temperature, 0.40 ml of water was added and the solids were filtered off, washed with chloroform and recrystallized from methanol-chloroform-diethyl ether, 435 mg, m.p. 263-265°C.

Eksempel 6 Example 6

Ved å anvende fremgangsmåten fra Eksempel 5 og starte med de passende reagenser, ble de følgende forbindelser fremstillet: Using the procedure of Example 5 and starting with the appropriate reagents, the following compounds were prepared:

Eksempel 7 Example 7

4-guanidino-N-(l-N-metylkarbamylbenzimidazol-2-yl)-benzamid (n = 0; R<1> = H; og 4-guanidino-N-(1-N-methylcarbamylbenzimidazol-2-yl)-benzamide (n = 0; R<1> = H; and

HET = 1-( N- metylkarbamvl) benzimidazol- 2- yl) HET = 1-(N-methylcarbamyl)benzimidazol-2-yl)

Det første produktet fra Eksempel 1 (600 mg, 1,81 mmol) og 520 mg (9,07 mmol) metylisocyanat ble tilsatt til 10 ml tørr N-metyl-2-pyrrolidon og dette ble rørt ved romtemperatur i 24 timer. Blandingen ble helt i 200 ml dietyleter og det resulterende bunnfall filtrert fra og kromatografert på silikagel med bruk av kloroform-metanol-eddiksyre (18:5:1; Vol:Vol:Vol) til utvasking. Fraksjonene som inneholdt produktet ble samlet, konsentrert i vakuum til tørrhet og resten gnidd med metanol, 76 mg, smp. 188-190°C. The first product from Example 1 (600 mg, 1.81 mmol) and 520 mg (9.07 mmol) of methyl isocyanate were added to 10 ml of dry N-methyl-2-pyrrolidone and this was stirred at room temperature for 24 hours. The mixture was poured into 200 ml of diethyl ether and the resulting precipitate was filtered off and chromatographed on silica gel using chloroform-methanol-acetic acid (18:5:1; Vol:Vol:Vol) for elution. The fractions containing the product were combined, concentrated in vacuo to dryness and the residue triturated with methanol, 76 mg, m.p. 188-190°C.

Eksempel 8 Example 8

Ved å bruke fremgangsmåten fra Eksempel 7 og starte med det første produktet fra Eksempel 2 og det nødvendige alkyleringsmiddel og base, ble de følgende forbindelser syntetisert: Using the procedure of Example 7 and starting with the first product of Example 2 and the required alkylating agent and base, the following compounds were synthesized:

Claims (1)

Analogifremgangsmåte for fremstilling av terapeutiskAnalogy method for the preparation of therapeutic aktive forbindelser med formelactive compounds of formula hvori HET er pyrimid-2-yl, dimetylpyrimid-4-yl, tiazol-2-yl, 4-fenyltiazol-2-yl, 4-fenyl-5-karbetoksytiazol-2-yl, 4-bifenylyltiazol-2-yl, pyrazin-2-yl, 6-klorpyrazin-2-yl, kinol-8-yl, 6-metoksykinol-8-yl, kinol-3-yl, l,3,4-tiadiazol-2-yl, 3-fenyl-1,2,4-tiadiazol-5-yl, 5-trifluormetyl-1,3,4-tiadiazol-2-yl, 5-metylisoksazol-3-yl, 5-klorpyrid-2-yl, 4,5-dicyano-imidazol-2-yl, 5-klorbenzoksazol-2-yl, indazol-5-yl, 2-karbetoksyindol-5-yl, 5-(p-nitrofenylsulfonyl)tiazol-2-yl eller et benzimidazol-2-yl med formelenwherein HET is pyrimid-2-yl, dimethylpyrimid-4-yl, thiazol-2-yl, 4-phenylthiazol-2-yl, 4-phenyl-5-carbethoxythiazol-2-yl, 4-biphenylylthiazol-2-yl, pyrazine -2-yl, 6-chloropyrazin-2-yl, quinol-8-yl, 6-methoxyquinol-8-yl, quinol-3-yl, 1,3,4-thiadiazol-2-yl, 3-phenyl-1 ,2,4-thiadiazol-5-yl, 5-trifluoromethyl-1,3,4-thiadiazol-2-yl, 5-methylisoxazol-3-yl, 5-chloropyrid-2-yl, 4,5-dicyano-imidazole -2-yl, 5-chlorobenzoxazol-2-yl, indazol-5-yl, 2-carbethoxyindol-5-yl, 5-(p-nitrophenylsulfonyl)thiazol-2-yl or a benzimidazol-2-yl of the formula der X er hydrogen eller metyl, Y er hydrogen, metyl, benzoyl, nitro, klor, fluor, brom eller metoksy og R<2> er hydrogen, ( C^ Cz) alkyl, fenetyl, N- ( C^ Cz) alkylkarbamylmetyl, N,N-di (Ci-Cs) alkylkarbamylmetyl, N- ( C^ Cz) alkylkarbamyl, ( Cx- Cz)alkoksykarbonylmetyl eller N-(p-klorbenzyl)-karbamyl-metyl; n er et helt tall fra null til 2; og R<1> er hydrogen where X is hydrogen or methyl, Y is hydrogen, methyl, benzoyl, nitro, chlorine, fluorine, bromine or methoxy and R<2> is hydrogen, (C^Cz)alkyl, phenethyl, N-(C^Cz)alkylcarbamylmethyl, N,N-di (C 1 -C 8 )alkylcarbamylmethyl, N-(C 1 -C 6 )alkylcarbamyl, (C 1 -C 6 )alkylcarbamylmethyl or N-(p-chlorobenzyl)carbamylmethyl; n is an integer from zero to 2; and R<1> is hydrogen eller ( C^ Cz) alkyl,or (C 1 -C 2 )alkyl, karakterisert ved acylering av en forbindelse med formelencharacterized by acylation of a compound of the formula med en benzosyre med formelenwith a benzoic acid of the formula hvori karboksylgruppen er aktivert som et syreklorid, blandet anhydrid eller aktiv ester, i et reaksjons-inert oppløsnings-middel i nærvær av en katalytisk mengde hydrokinon ved en reaksjonstemperatur på 20-180°C, og derefter eventuelt, når en benzimidazol-2-yl gruppe med formel (II) ønskes som HET, hvor R<2> er forskjellig fra hydrogen, omsetning av en tilsvarende forbindelse med formel (I) hvor R<2> er hydrogen, med (a) når R<2> er N-(C-l-C3 ) alkylkarbamyl, et tilsvarende isocyanat med formel (C-L-C3) alkylisocyanato, og (b) når R2 er (^-03) alkyl, fenetyl, N- (^-03) alkylkarbamylmetyl , N, N-di (C-L-C3) alkylkarbamylmetyl, (C-L-C3) alkoksykarbonylmetyl eller N(p-klorbenzyl)-karbamylmetyl, et tilsvarende alkyleringsmiddel med formel R<2->Z hvor Z er Cl eller Br,wherein the carboxyl group is activated as an acid chloride, mixed anhydride or active ester, in a reaction-inert solvent in the presence of a catalytic amount of hydroquinone at a reaction temperature of 20-180°C, and then optionally, when a benzimidazol-2-yl group of formula (II) is desired as HET, where R<2> is different from hydrogen, reaction of a corresponding compound of formula (I) where R<2> is hydrogen, with (a) when R<2> is N- (C-l-C3 ) alkylcarbamyl, a corresponding isocyanate of formula (C-L-C3) alkylisocyanato, and (b) when R2 is (^-03) alkyl, phenethyl, N-(^-03) alkylcarbamylmethyl, N, N-di ( C-L-C3) alkylcarbamylmethyl, (C-L-C3) alkoxycarbonylmethyl or N(p-chlorobenzyl)-carbamylmethyl, a corresponding alkylating agent of formula R<2->Z where Z is Cl or Br, og eventuelt fremstilling av et farmasøytisk godtabart salt av produktet.and optionally producing a pharmaceutically acceptable salt of the product.
NO892058A 1988-05-24 1989-05-23 Analogous Procedures for the Preparation of Therapeutically Active Benzamides NO173867C (en)

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